A great cover story from BioCentury yesterday talks about changes both industry sponsors and the FDA need to make in order to improve the drug development process. The key? Engage the patient community, something PPMD and the Duchenne community have been encouraging for years. As described in the article, PPMD’s benefit-risk project continues to be hailed as an example of what needs to be done to provide regulatory and industry with the data they need to do their jobs efficiently and effectively. Today, PPMD will host a Congressional briefing in D.C. emphasizing this very notion – listen to the patients and parents. Stay tuned for more about today’s briefing and read this great article.
What industry, FDA must do to realize the potential of patient engagement
Calming the pendulum
By Steve Usdin, Washington Editor
Published on Monday, February 23, 2015
Regulators and drug developers have converged on the idea that enhancing and broadening patient engagement is a key to improving drug development and adjudicating controversies over benefit-risk decisions and the value of medicines.
While the idea of patient engagement dates back to AIDS activists in the 1980s, the current iteration emphasizes collaboration over confrontation, and is moving away from protest and toward quantifiable metrics and peer-reviewed social science methods.
The goal is to move beyond sporadic involvement at specific points on the product development continuum and to systematically integrate distilled insights from patient experiences and perceptions throughout the process, including the target product profile and endpoints used in clinical development.
Making patients true partners thus would help create better medicines and reduce skepticism about regulators and the animus that has destroyed public trust of the pharmaceutical industry.
For companies, engaging with patients can help determine which products to develop, how to study them and how they could be used. Patients can also help define the value of medical interventions for payers in ways that are far more compelling than drug developers can.
By quantifying risk-tolerance, patient engagement could also help calm the pendulum that has been swinging for 20 years between permissive policies designed to speed new therapies to the market and stricter requirements intended to minimize safety risks.
For regulators, patients and their advocates can help inform and legitimize regulatory decisions by showing how those decisions reflect the interests and preferences of people living with diseases.
And patients can multiply the effectiveness of regulators and investment in medical research, for example by drafting FDA guidance documents and by directing money and organizational efforts toward targeted R&D.
To realize this potential, patient engagement must move beyond current approaches — which rely too much on anecdotes and personal testimony — to develop and validate methods that produce reliable, scientifically rigorous data.
To do so, the key challenges include reaching agreement on best practices for patient engagement, and providing advocacy organizations the financial and technical resources they need without imperiling their independence and credibility.
Patient advocates, FDA and drug companies are starting to create rules of the road. Patient engagement is industry's top priority for PDUFA reauthorization, the first topic addressed in the House Energy & Commerce Committee's 21st Century Cures legislative discussion draft, and a high priority for outgoing FDA Commissioner Margaret Hamburg and the directors of the agency's centers for drugs and devices.
Patient engagement provisions in the 21st Century Cures discussion draft were written based on input from patient groups, industry and FDA. They are intended to create regulatory certainty around the use of patient perspectives, including formal pathways for patient groups and companies to submit information about patient preferences, as well as defining how FDA will incorporate these submissions into approval and other decisions.
The agency already has established proof of principle for the process by issuing its first approval based on patient-centered criteria. In January, the Center for Devices and Radiological Health (CDRH) approved a new weight loss device, the Maestro Rechargeable System from EnteroMedics Inc., based on the division's Patient Preference Initiative.
From town halls to templates
Patient engagement was a major focus of the 2012 PDUFA V reauthorization, which mandated the creation of a Patient Focused Drug Development program at FDA.
The public face of the program has been a series of meetings to solicit patient perspectives about specific diseases. But it isn't possible to organize town hall meetings for every disease and condition, and there are limits to the utility of information that can be collected through public testimony.
FDA and the public have little if any information about how well the experience of the patients who testify at meetings reflects the experiences of other patients. Selection bias is a concern because patients who are too ill, lack financial resources or fear stigmatization may not attend the meetings.
Even if the testimony is broadly representative, there is no obvious way to structure the information so it can be used by regulators. FDA's reports about patient meetings are not stored in searchable databases, and the information collected would not meet inclusion criteria for evidence-based reviews.
"There is a lot of value in hearing directly from patients what their experience is to get a sense of what it means to live with a disease, the burden of disease and treatment goals," Kristin Van Goor, assistant VP of scientific and regulatory affairs at PhRMA, told BioCentury. The next step, she said, is to "translate those anecdotes into tools, things we can measure."
One of the places FDA could apply patient experience is in a benefit-risk template it is developing to help make and explain drug approval decisions. The template aims to employ a set of "decision factors" to standardize the way reviewers consider benefit and risk for new drugs and biologics. These include assessments of the severity of the condition the drug is meant to treat, the available treatments, clinical data on both benefit and risk, and efforts that could help mitigate risks after approval.
The National Health Council, an umbrella group for patient advocacy organizations, is working with BIO and PhRMA to develop methods for linking data on patient preferences to FDA's framework, according to Marc Boutin, NHC's EVP and COO.
Creating better ways to integrate patient perspectives into the decisions made by FDA and drug developers will be BIO's top priority for PDUFA reauthorization, according to Paul Hastings, the chairman and CEO of OncoMed Pharmaceuticals Inc. who chairs BIO's Patient Advocacy Committee.
"We want to focus this time around on building patient-centered drug development into the regulatory system, and into drug discovery and development," Hastings told BioCentury. "We want to turn this into a science rather a qualitative, subjective analysis."
To do so, he said, "We have to define what we mean by patient engagement, learn what patient advocacy organizations want, and come up with a recommendation for the science of patient engagement." The goal is to learn "what advocates can input into the process that will help FDA and companies come out of the drug development and discovery process with a better product for patients."
Stated preference methods
Industry, FDA and patient advocates won't have to look far to find science to determine and quantify patient preferences, according to John F. P. Bridges, an associate professor at the Johns Hopkins Bloomberg School of Public Health who researches qualitative and quantitative methods to learn about patient preferences. FDA will, however, need to change the way it thinks about risk tolerance, he said.
"FDA acknowledges there is a benefit-risk trade-off for different conditions," Bridges noted. "This is good. The problem is they have been using disease severity as a proxy. Knowing how bad a disease is doesn't necessarily help you calculate a benefit-risk trade-off."
For example, patients with chronic conditions that are not life-threatening may be willing to accept more risk in exchange for the possibility of symptom relief than regulators assume. And individuals may be willing to trade a small increase in the chance of having a heart attack for access to a drug that eliminates pain.
Instead of assuming that patients with more severe diseases, such as cancer, are willing to accept higher risks than those suffering from less deadly conditions, Bridges advocates methods to measure risk tolerance that employ well-established research tools to quantify consumer preferences.
Since the late 1970s, most industries that sell products to consumers have been using a set of tools called conjoint analysis or stated preference methods to guide product development and marketing.
"Stated preference methods use techniques grounded in economics and psychology to try to understand how people make trade-offs when they are making decisions," Bridges said. "These are mechanisms for identifying value. They are not an oracle to perfectly see the future, but they are better than nothing."
A car company might use stated preference methods to determine how much engine power a customer is willing to sacrifice to gain a specific increment of fuel efficiency.
In the healthcare context, stated preference methods could be used "to analyze how much side effects patients will accept before they don't want more chemotherapy," Bridges said. It isn't a simple question, because "there are multiple benefits and multiple harms" that have to be considered.
Although the science of measuring preferences is well developed, the methods are not simple, and poor study design or implementation can yield inaccurate or misleading results.
One potential pitfall involves averaging or pooling results.
"A recent study looked at gender preferences for physicians of homeless women in shelters," Bridges noted. "On average there was no preference, but when you looked at it, half wanted a male and half wanted a female," so the average concealed strong, heterogeneous preferences.
Proof of principle
CDRH already has demonstrated that the idea of patient preference can be turned into action. When FDA approved EnteroMedics' Maestro Rechargeable System, an implantable electrical stimulation system to treat obesity, it cited quantitative patient risk-tolerance data that was obtained through a stated preference survey (see "Virtuoso Approval," page 3).
"What the devices division did is what we are trying to work with Janet Woodcock to do on drugs," Hastings told BioCentury. Patients can tell FDA, "Here's the benefit I'd like to derive and here's the risk I'm willing to have."
"The fact that CDRH actually made a decision based on preference data changed the world," Bridges said.
The world cannot, however, rely on FDA to produce comprehensive data about patient preferences.
Just as FDA could never hold formal meetings to solicit patient testimony about every serious disease, the agency will never have the resources to conduct stated preference surveys for every serious medical condition.
"Who is going to do all these studies? We have a slight workforce problem," Bridges said.
The solution is for FDA to develop standards for assessing patient-preference data submitted by third parties, including drug developers and patient advocacy organizations.
At least one advocacy group has conducted a preference study that yielded potentially actionable insights and could serve as proof of concept for third parties to submit information on patient preferences to FDA.
Bridges helped the patient advocacy organization Parent Project Muscular Dystrophy design and implement an online survey that asked people who take care of children with Duchenne muscular dystrophy (DMD) to rank a variety of options on a best-worst scale. According to a paper the group published in Clinical Therapeutics, "Caregivers attributed very high scores to stopping or slowing the progression of muscle weakness."
The survey also revealed that improvement in quality of life is more important to caregivers than extending life span, and that caretakers are willing to accept serious risks to achieve quality of life improvements. For the DMD caregivers surveyed, "having additional postapproval data was relatively the least important attribute," the paper said.
Rules of the road
Including caregiver preferences in the calculus does point to key decisions that will have to be made for the new paradigm to work: deciding who speaks for patients, and establishing rules for relationships between drug companies and patients and patient advocacy groups.
Rather than try to forge relationships with individual patients, it is far easier for regulators and drug companies to interact with organized patient advocacy groups, especially those that have scientific and medical expertise.
But while advocacy groups can be valuable intermediaries, there are instances when companies need to interact directly with patients, according to the National Health Council's Boutin. "We've been so long the surrogate for the patient perspective that we think we own it and know it all. We know a lot, but we aren't the end and the beginning," he said.
Drug companies will also want assurances that they will not run into conflict with existing strictures on communications with the public.
"Whereas clear and comprehensive engagement frameworks are in place for direct engagement with healthcare professionals, such guidance does not yet exist for engagement with patients," Lode Dewulf, VP and chief patient affairs officer at UCB Group, wrote in a paper published in Therapeutic Innovation & Regulatory Science.
In the context of prohibitions on direct-to-consumer advertising outside the U.S., he said, "pharma companies have historically simplified the message 'do not promote to patients' into 'do not talk to patients.'"
Dewulf outlined numerous reasons why drug companies should interact with patients, and described policies UCB has implemented to ensure that patient privacy is protected and interactions with patients are not promotional.
FDA should issue guidance "on what is acceptable for high-quality patient engagement that creates a framework for companies to work with patients in ways that will pass FDA's 'sniff test,'" Tanisha Carino, EVP at Avalere Health LLC, told BioCentury.
Financing patient engagement
In addition to guidance on interactions with individual patients, rules of the road are needed for financial interactions between medical product manufacturers and patient groups.
Carino argued that industry or preferably government funding is needed to help patient groups recruit, train and retain staff who can engage as equals with FDA and industry. "It is indisputable that in order for the patient community to have the level of engagement we are all hoping for takes a lot of human capital investment, and this is not cheap," she said.
Money, however, can cause as many problems as it solves. Even the best data will be of little use if it is tainted by real or perceived conflicts of interest.
"Within industry there is a lot of hesitancy to provide money that can be seen as providing an inducement to the patient community," according to Carino. "That leaves a chasm in terms of the funding that is needed" to support patient engagement.
Meanwhile, patient groups receive and in some cases aggressively solicit financial support from medical product developers. Given that even tenuous financial ties to a drug company can prevent a scientist or clinician from serving on an FDA advisory committee, the links between advocacy organizations and regulated industry are certain to come under scrutiny if patient engagement were to be integrated into regulatory decision-making.
Even if patient groups are not providing advice about approvals of specific products, skeptics will warn that the kinds of questions they include in surveys, the endpoints they promote and other types of advice given to FDA could help corporate donors or hurt their competitors.
FDA and patient groups could proactively address those concerns by crafting rules for ensuring the independence of patient groups.
In addition to creating guidelines for companies to interact with patients and patient advocacy groups, FDA could take other steps to facilitate patient engagement.
Some companies say they need explicit assurances that FDA will not treat the collection of data about patient preferences as marketing an unapproved product, according to Boutin.
He said FDA also should issue guidance that will provide predictability on how patient-preference information will be used in making regulatory decisions. "If FDA does that, every company will start to collect this information. It doesn't have to be mandated," he said.
Van Goor also thinks FDA should issue guidance on patient preference data. "One of the things that needs to happen is increased certainty about how these types of data can be used for decision-making. How will FDA view these kinds of studies? How can they be used to inform the selection of endpoints? At what point in the drug development process can you have discussions with FDA? It comes down to regulatory certainty and predictability," she said.
Reshaping drug development
While patient perspectives can help improve decisions made near the end of the development continuum when companies are seeking FDA approval, patient engagement would be more valuable if it came earlier, according to Boutin.
Drug companies often approach patient groups too late, he said. "What happens currently is they get a product into Phase III and then want us to stand up and say the benefit-risk is worth it for patients. We haven't been part of the discussion until that point. If we were involved at the beginning, the product may not have been developed."
OncoMed's Hastings agreed that patients can help companies improve the chances that they are developing products that will be successful. "It makes perfect sense to build benefit-risk analysis into drug discovery and development so at the end of a billion-dollar process you have a drug people find acceptable," he said.
PhRMA's Van Goor also thinks that quantified patient preferences can shape drug development. "As you get more quantitative, it is possible to use those data earlier in the development process to make decisions about endpoints, types of information you are going to collect, and to use it to shape the development program," she said.
Patient preference data could "perhaps result in different kinds of drugs being developed," or lead companies to change the indications they study, Van Goor said. "It comes down to: Is there something you can measure? Is it reliable, accurate, and meaningful? If you can answer those questions, you open the up the world of things that could be invented."
Patient preference data also could lead drug developers and regulators to reconsider their assumptions about clinical efficacy, according to Van Goor. "As you think about defining what is meaningful, you can ask questions like: Is decreasing nausea meaningful? Is addressing fatigue meaningful? And then you can start to understand if those symptoms were addressed, would that mean a person could go to work, or a child could go to a regular school?"
Efforts to integrate patient experiences into drug development and regulation resonate with wider changes in the healthcare environment, including the proliferation of personal health tracking technologies, shifting greater financial responsibility to patients, the establishment of virtual patient communities on social media platforms and demands for greater access to experimental medicines.
Boutin believes that, over time, patient engagement could change the way payers evaluate drugs.
"If you start to use patient preference data from the very beginning throughout the life cycle of the product, you start to define value in a new and different way. This has implications for coverage and reimbursement," he said.
Patient preference data could be particularly important in defining quality measures that, like readmission rates and other quality metrics, will increasingly be used by payers, Boutin said.
Patient perceptions will also be selling points as more costs, and decisions, are shifted to patients.
"A high-value product that addresses a patient preference issue is more likely to find a receptive marketplace," Boutin said.
Companies and Institutions Mentioned
Avalere Health LLC, Washington, D.C.
Biotechnology Industry Organization (BIO), Washington, D.C.
EnteroMedics Inc. (NASDAQ:ETRM), St. Paul, Minn.
Johns Hopkins University, Baltimore, Md.
National Health Council (NHC), Washington, D.C.
OncoMed Pharmaceuticals Inc. (NASDAQ:OMED), Redwood City, Calif.
Parent Project Muscular Dystrophy, Hackensack, N.J.
Pharmaceutical Research and Manufacturers of America (PhRMA), Washington, D.C.
UCB Group (Euronext:UCB), Brussels, Belgium
Dewulf, L. "Patient engagement by pharma — Why and how?" Therapeutic Innovation & Regulatory Science (2015)
Ho, M. "Incorporating patient-preference evidence into regulatory decision ...." Surgical Endoscopy (2015)
O'Callaghan, K. and Shuren, J. "Listening to patients' views on new treatments for obesity."FDA Voice (2015)
Peay, H., et al. "A community-engaged approach to quantifying caregiver preferences ...Clinical Therapeutics (2014)
Schaeffer, S. "Reframing FDA." BioCentury (2013)